Reporting of MMR evidence in professional publications: 1988-2007.

OBJECTIVE: To examine how journals and magazines disseminate research evidence and guidance on best practice to health professionals by aligning commentaries on measles, mumps, and rubella vaccine (MMR) evidence in journals with key events in the MMR controversy. DESIGN: Content analysis. DATA SOURCES: Comment articles in six commonly read UK publications. MAIN OUTCOME MEASURES: Number of comment pieces by publication, year and article type; trends in the focus, tone and inclusion of recommendations on MMR. RESULTS: 860 articles met the inclusion criteria (BMJ n = 104, Community Practitioner n = 45, Health Visitor n = 24, Practice Nurse n = 61, Nursing Standard n = 61 and Pulse n = 565). Of these 860 comment pieces, 264 made some reference to evidence endorsing the safety of MMR. Around one in 10 were rated as negative (10.9%, n = 29) or neutral (11.3%, n = 30) in relation to MMR safety, and nearly a quarter (22.7%, n = 60) were rated as mixed. Following the publication of Wakefield et al's 1998 paper there was a period of neutrality. In 2000, despite growing public concerns and widespread media coverage, fewer than 20 comment pieces were published. Less than a quarter of comment pieces (n = 196, 22.7%) included recommendations. CONCLUSION: While a period of neutrality may reflect a professional response to uncertainty by holding back until consensus emerges, it may also represent a missed opportunity to promote evidence-based practice.

Increased plasma tryptophan in HIV-infected patients treated with pharmacologic doses of nicotinamide.

OBJECTIVE: Decreased plasma tryptophan in persons infected with human immunodeficiency virus (HIV) was first reported over a decade ago, and this observation has since been confirmed by many groups. Before this study, only zidovudine (an antiviral medication) had been reported to reverse plasma tryptophan depletion in HIV-infected persons. Starting with the hypothesis that HIV induces a pellagra-like state and that plasma tryptophan in HIV-infected patients is decreased as a known biochemical correlate of pellagra, we predicted that niacin therapy would reverse plasma tryptophan depletion as it does in pellagra. METHODS: After receiving approval from the institutional review board, we treated HIV-infected patients for 2 mo with high-dose niacin in the form of oral nicotinamide. RESULTS: There was an average 40% increase in plasma tryptophan (P = 0.01) in the four HIV-infected individuals who completed the 2-mo protocol. This finding was specific in that four other amino acids, which have been shown to have significant plasma concentration alterations during HIV infection (i.e., cystine, methionine, taurine, and lysine), showed no significant change with nicotinamide therapy. CONCLUSIONS: There were no adverse side effects attributable to this treatment. The effects of high-dose nicotinamide treatment on morbidity or mortality in HIV-infected persons are yet to be determined. This report marks the first successful use of a vitamin to reverse this HIV-induced metabolic abnormality.

Pacemakers and defibrillators for congestive heart failure.

Although medical therapy is the primary therapy for patients with heart failure, the use of pacemakers to improve cardiac hemodynamics is under investigation. Despite promising initial results, controlled studies have not verified the benefit of application of VDD or DDD pacing to a nonselected population of severely symptomatic congestive heart failure (CHF) patients to simply shorten their atrioventricular (AV) delay. There is increasing interest in pacing the left side of the heart or simultaneously pacing the right and left ventricles. Early studies suggest that these techniques may produce favorable hemodynamic effects in patients with CHF. Controlled, randomized studies are now underway. Further, it has been shown that sudden cardiac death accounts for 50% of deaths in patients with CHF. The value of an implantable cardioverter defibrillator (ICD) in secondary prevention of sudden cardiac death is well established. The use of ICD for primary prevention of sudden cardiac death in patients with CHF is being actively evaluated. Several large multicenter trials are underway, some combined with biventricular pacing, and should provide useful data in the coming years.

The impact of recent ion channel science on the development and use of antiarrhythmic drugs.

In the past 20 years in the basic laboratory, tools have been developed to further our understanding of the mechanism of arrhythmias and of the effect of compounds on these or their substrates. Patch clamp studies have better defined the cardiac channels. A new classification of antiarrhythmic drugs was devised, coined the Sicilian Gambit. Drugs, aimed at blocking specific channels, are now being developed. With the cloning of channels, information about their molecular structure became available. One can begin to understand the molecular determinants of antiarrhythmic drug action on specific ion channels, and how this is modulated by effectors. Molecular and electrophysiologic techniques also have been used to collect information about the way disease states affect the cardiac channels, and how this can alter the response to ion channel blockers. This has proceeded utilizing a few technologies. Diseased heart cells from patients, from animal models of disease, or from transgenic mice are studied to examine the change in current expression and channel protein quantity in different stages of disease. Hopefully this new information will make drug therapy more target-oriented.

Variable effects of adenosine on retrograde conduction in patients with atrioventricular nodal reentry tachycardia.

Adenosine has been demonstrated to reliably produce transient block of atrioventricular nodal (AVN) conduction, and has been advocated as a method of differentiating retrograde conduction via the atrioventricular node from accessory pathway conduction. However, the response of retrograde AVN to adenosine in patients with typical atrioventricular nodal reentry tachycardia (AVNRT) remains unclear. We evaluated 13 patients (mean age 45 +/- 20 years) with typical AVNRT prior to AVN modification. During right ventricular pacing, a rapid bolus of adenosine (0.2 mg/kg; maximum 18 mg) was administered. Adenosine sensitivity, defined by transient ventriculoatrial block, was observed in six patients, while in seven patients ventriculoatrial conduction was unaffected. An adenosine bolus administered during sinus rhythm or atrial pacing resulted in antegrade atrioventricular block in all the adenosine resistant patients in whom this was performed (n = 6). Comparisons of AVN electrophysiological characteristics between the adenosine sensitive and adenosine resistant patients were performed. There was no difference with respect to ventriculoatrial effective refractory period, ventriculoatrial Wenckebach, AVNRT cycle length, and His to atrial echo interval in AVNRT. However, there was a trend toward a longer antegrade fast pathway ERP in the adenosine sensitive group (P = 0.07). Electrophysiological properties do not predict retrograde AVN adenosine sensitivity. Adenosine does not cause retrograde AVN block in all patients with AVNRT, and therefore cannot reliably distinguish between retrograde conduction via the AVN or an accessory pathway.

Identification of Beck Depression Inventory items related to multiple sclerosis.

The percentage contribution of each item on the Beck Depression Inventory (BDI) to the total BDI score was compared across patients with multiple sclerosis (MS), patients diagnosed with major depressive disorder, and normal college students. We considered an item to be confounded by MS-related symptoms if its percentage contribution to the total BDI score was significantly greater in the MS group than the major depression and control groups. Items measuring work difficulty, fatigue, and concerns about health met this criterion. These items accounted for 34, 17, and 19% of the total BDI score in the MS, major depression, and control groups, respectively. Using the 18-item BDI (BDI-18) which resulted from excluding the 3 confounded items, MS patients found to be were more depressed than controls but less depressed than the major depression group. The identification of signs of depression not confounded with MS which could be substituted for confounded signs was also discussed.

The acute treatment of supraventricular tachycardia.

The diagnosis of supraventricular tachycardia has become much more important with the advent of radiofrequency ablation. This is usually best done at presentation in an acute setting. A 12-lead electrocardiogram should be a routine aid in making the diagnosis. A continuous rhythm strip must be obtained during administration of adenosine and at the termination of tachycardia. Most recent treatment guidelines would include adenosine as first-line therapy. If adenosine fails to restore normal sinus rhythm, diltiazem or a beta blocker should then be considered. If there is significant heart failure, digoxin may be useful. In the presence of wide complexes, agents that produce atrioventricular nodal block should be avoided.

A recombinant inwardly rectifying potassium channel coupled to GTP-binding proteins.

GTP-binding (G) proteins have been shown to mediate activation of inwardly rectifying potassium (K+) channels in cardiac, neuronal and neuroendocrine cells. Here, we report functional expression of a recombinant inwardly rectifying channel which we call KGP (or hpKir3.4), to signify that it is K+ selective, G-protein-gated and isolated from human pancreas. KGP expression in Xenopus oocytes resulted in sizeable basal (or agonist-independent) currents while coexpression with a G-protein-linked receptor, yielded additional agonist-induced currents. Coexpression of KGP and hGIRK1 (a human brain homolog of GIRK1/Kir3.1) produced much larger basal currents than those observed with KGP or hGIRK1 alone, and upon coexpression with receptor, similarly large agonist-induced currents could be obtained. Pertussis toxin treatment significantly diminished agonist-dependent currents due to either KGP or KGP/hGIRK1 expression. Interestingly, PTX also significantly reduced basal KGP or KGP/hGIRK1 currents, suggesting that basal activity is largely the result of G-protein gating as well. When the two channels were coexpressed with receptor, the relative increase in current elicited by agonist was similar whether KGP and hGIRK1 were expressed alone or together. When in vitro translated or when expressed in Xenopus oocytes or CHO mammalian cells, KGP gave rise to a nonglycosylated 45-kD protein. Antibodies directed against either KGP or hGIRK1 coprecipitated both proteins coexpressed in oocytes, providing evidence for the heteromeric assembly of the two channels and suggesting that the current potentiation seen with coexpression of the two channel subunits is due to specific interactions between them. An endogenous oocyte protein similar in size to KGP was also coprecipitated with hGIRK1.

Sinus node reentrant tachycardia.

This review article discusses the electrophysiological basis of sinus node reentry, clinical features of sinus node reentry, and the management of this uncommon tachycardia with drugs and ablative therapy. It also proposes the use of the term "sinoatrial reentrant tachycardia" for this form of tachycardia.

Flumazenil (Ro15-1788) does not affect ethanol tolerance and dependence.

There are conflicting reports concerning whether flumazenil (Ro15-1788) can antagonize the central effects of ethanol and ethanol withdrawal reactions. C57BL/6J mice were treated chronically with an ethanol liquid diet. Control mice were pair fed an isocaloric diet containing no ethanol. These mice were injected with either Ro15-1788 (25 mg/kg) or vehicle immediately before, 14 h or 24 h before ethanol withdrawal. Under these conditions, no attenuation of the severity of handling-induced withdrawal seizures or of withdrawal hypothermia was observed in the ethanol-dependent mice injected with Ro15-1788. Likewise, there was no abolition or attenuation of tolerance to the ataxic effects (sleep time and horizontal dowel tests) and hypothermic effects of ethanol by Ro15-1788 when the mice were tested on day 3 of ethanol withdrawal. It is concluded that Ro15-1788 (25 mg/kg) has no effect on ethanol tolerance and dependence.

The ability of chlordiazepoxide to maintain ethanol tolerance and dependence.

Two criteria need to be satisfied in the demonstration of cross-dependence to chlordiazepoxide (CDP) in ethanol-dependent mice. These are the ability of CDP to suppress ethanol withdrawal and to maintain the dependent state. In this study, mice which had been fed chronically an ethanol diet followed by two days of CDP diet treatment had more severe CDP withdrawal signs induced by Ro15-1788 than drug-naive mice which were similarly exposed to the CDP diet treatment. The data indicate that CDP can maintain the dependent state acquired from the prior ethanol treatment. Alternatively, the prior ethanol treatment would have facilitated the development of CDP dependence, but it was not deemed likely. Three behavioral tests, namely, runway, sleep time, and drug-induced hypothermia, were used to test whether CDP could maintain the ethanol tolerance acquired from the prior ethanol treatment. The runway test showed that CDP could maintain the previously acquired ethanol tolerance. However, interpretations of the data from the sleep time and hypothermia tests are more equivocal because of factors such as peak tolerance, differential rates of development and dissipation of ethanol (or CDP) tolerance as determined by different behavioral tests.

A histologic evaluation of the accuracy of TMJ diagnostic arthroscopy.

Sixty-seven temporomandibular joints with internal derangement were examined with arthroscopy, and synovial biopsies were taken for histologic evaluation. Histologically, in 10 cases, the synovium appeared to be normal in appearance, 24 cases had moderate to severe synovitis, 11 cases showed hyperplastic synovitis, 13 cases showed synovial fibrosis, and foreign body granuloma was found in 9 cases. Correlation between arthroscopic observation and histologic findings disclosed an 89.1% specificity and 100% sensitivity.

Chronic treatment with ethanol or chlordiazepoxide alters the metabolism of chlordiazepoxide.

Although chronic ethanol administration in C57BL/6J mice did not cause an induction of ethanol metabolism, it altered the metabolism of chlordiazepoxide (CDP). Significantly lower blood levels of CDP, but higher levels of N-desmethyl CDP (NDCDP), were observed in ethanol-dependent mice compared to pair-fed controls during the first hour after CDP injection. Mice treated chronically with CDP showed significantly lower blood levels of CDP and NDCDP than pair-fed controls after a test dose of CDP. In response to an injection of ethanol, the CDP-dependent mice had lower blood alcohol levels (BAL) than the pair-fed controls, but the rate of fall of BAL was not different in the two groups. Thus, chronic CDP treatment affected the absorption and distribution of ethanol. These results provide a metabolic basis for the manifestations of CDP tolerance and ethanol cross-tolerance that have been reported in CDP-dependent mice.

Partial cross-dependence on ethanol in mice dependent on chlordiazepoxide.

Mice which had been fed chronically a liquid diet containing chlordiazepoxide (CDP) showed spontaneous and Ro15-1788-induced withdrawal signs upon CDP withdrawal. Ethanol (1.5 g/kg) injected 5 min before Ro15-1788 injection almost completely suppressed the withdrawal signs induced by the benzodiazepine receptor antagonist. However, neither ethanol injection nor ethanol diet administration could prevent the loss of appetite and weight loss on day 1 of CDP withdrawal. Likewise, the addition of saccharin in the ethanol diets did not prevent the loss of appetite. Mice which had been fed the CDP diet followed by 9 days of ethanol treatment (CDP/ethanol) showed more severe hypothermia during ethanol withdrawal compared to mice which had been fed the control/ethanol diets. The CDP/ethanol mice also retained the increase in runway activity attained from the prior CDP treatment. The data indicate that CDP-dependent mice showed partial rather than full cross-dependence on ethanol.

A liquid diet model of chlordiazepoxide dependence in mice.

Mice fed chronically (3 to 4 weeks) a liquid diet containing chlordiazepoxide (CDP) became physically dependent on the drug as demonstrated by the occurrence of withdrawal signs precipitated by injection of the benzodiazepine antagonist Ro15-1788 (5 to 25 mg/kg) or by omitting CDP from the diet (spontaneous withdrawal). Very low blood concentrations of CDP, but medium to high levels of the active metabolites N-desmethyl CDP and demoxepam were found during the period of CDP administration. The Ro15-1788-induced withdrawal signs appeared within 1 min after the injection of the antagonist and lasted for at least 10 min. Quantifiable withdrawal signs included tail lift, tremor, impaired movement and handling-induced seizures. Mice undergoing spontaneous withdrawal had milder withdrawal signs such as weight loss, in appetite and suppression of runway and head-dipping activities on day 1 or day 2 of withdrawal. These signs were also present in Ro15-1788-induced withdrawal. A long-lasting rebound increase in runway and head-dipping activities occurred several days after CDP withdrawal.